The overall goal of this research plan is to understand the significance of differences between human and mouse Toll-like receptor 9 (TLR9). Both the specificity of TLR9 and its expression among immune cells differ between these species, making it difficult to extend mouse studies of TLR9 function into humans. In this proposal, a human TLR9 transgenic cassette will be used to create mouse strains expressing human TLR9 or mouse TLR9 with the human expression pattern. The function of TLR9 in these mice will be evaluated using a number of criteria. PUBLIC HEALTH RELEVANCE: There is considerable clinical interest in using synthetic ligands of Toll-like receptor 9 (TLR9) to treat infectious disease, generate better vaccines, and alleviate symptoms of allergy or asthma. Unfortunately, differences in the function of TLR9 in humans and mice have made it difficult to assess the efficacy of such approaches in animal models other than non-human primates. This proposal focuses on creating and characterizing "humanized" TLR9 mice that will enable the comparison of TLR9 function between humans and mice.